1. Field of the Invention
The present invention is in the field of biomedical optics. In particular, this invention pertains to the measurement of physiological function of multiple organs or tissues at once.
2. Description of the Background Art
Simultaneous assessment of physiological function of many organs at the same time is always desirable and often necessary. It is particularly important in the case of critically ill or injured patients because a large percentage of these patients face the risk of multiple organ failure (MOF) resulting in death (C. C. Baker et al., Epidemiology of Trauma Deaths, American Journal of Surgery, 1980, 144-150; R. G. Lobenhoffer et al., Treatment Results of Patients with Multiple Trauma: An Analysis of 3406 Cases Treated Between 1972 and 1991 at a German Level I Trauma Center, Journal of Trauma, 1995, 38, 70-77). MOF is a sequential failure of lung, liver, and kidneys and is incited by one or more severe causes such as acute lung injury (ALI), adult respiratory distress syndrome (ARDS), hypermetabolism, hypotension, persistent inflammatory focus, or sepsis syndrome. The common histologic features of hypotension and shock leading to MOF include tissue necrosis, vascular congestion, interstitial and cellular edema, hemorrhage, and microthrombi. These changes affect the lung, liver, kidneys, intestine, adrenal glands, brain, and pancreas (in descending order of frequency) (J. Coalson, Pathology of Sepsis, Septic Shock, and Multiple Organ Failure. In New Horizons: Multiple Organ Failure, D. J. Bihari and F. B. Cerra, (Eds). Society of Critical Care Medicine, Fullerton, Calif., 1986, pp 27-59). The transition from early stages of trauma to clinical MOF is marked by the extent of liver and renal failure and a change in mortality risk from about 30% to about 50% (F. B. Cerra, Multiple Organ Failure Syndrome. In New Horizons: Multiple Organ Failure, D. J. Bihari and F. B. Cerra, (Eds). Society of Critical Care Medicine, Fullerton, Calif., 1989, pp 1-24).
Hepatic function (i.e., liver function) is difficult to assess in any patient population and particularly in the critically ill population. Currently no measure of "liver function" such as serum transaminase serum GGT, or serum alkaline phosphatase actually indicates the real-time function of the liver or its enzyme systems. Moreover, other tests such as serum glucose, prothrombin time, serum albumin, serum bilirubin, and others indicate the function of the liver on a longer time scale and do not necessarily correlate with immediate clinical conditions. Other studies have shown that even in normal patients other interventions commonly performed in the intensive care unit, such as mechanical ventilation, can adversely affect liver function even in the absence of true hepatic injury. Additionally, "liver function" is actually the conglomeration of many different functions depending on many different enzyme and cellular systems within the liver.
Current clinical practice for the assessment of liver function is based solely upon intermittent blood sampling and the measurement of numerous circulating enzymes and other chemical entities which indirectly imply the nature of both synthetic and elimination functions of the liver. These include coagulation tests, measurements of serum albumin, measurement of serum bilirubin and its conjugated form, and the measurement of serum values for enzymes known to be contained within hepatocytes and bile canalicular cells (J. B. Henry (Ed). Clinical Diagnosis and Management by Laboratory Methods, 17th Edition, W. B. Saunders, Philadelphia, Pa., 1984); G. P. Zaloga and D. S. Prough, Monitoring Hepatic Function, Critical Care Clinics, 1988, 4, 591-603; W. D. Figg et al., Comparison of Quantitative Methods to Assess Hepatic Function: Pugh's Classification, Indocyanine Green, Antipyrine, and Dextromethorphan, Pharmacotherapy, 1995, 15, 693-700; R. Jalan and P. C. Hayes, Quantitative Tests of Liver Function, Aliment Pharmacol. Ther., 1995, 9, 263-270). However, these data are discontinuous, have no real-time implications, are cumbersome to repeat, and can, under certain circumstances (such as in patients with cirrhosis), be extremely misleading. For example, patients with previously healthy livers who take in a toxic ingestion may have profound elevations in serum transaminases but still may have significantly preserved liver function. Conversely, patients with cirrhosis may suffer a serious hepatic insult with minimal elevation in their serum transaminases and yet have almost no hepatic reserve. Additionally, there are patients whose changing hepatic function is key both to their management and ultimately to their survival. These include patients with toxic ingestion and patients with deteriorating liver function for other reasons such as porto-systemic encephalopathy, TIPPS placement, and simple mechanical ventilation which is known to specifically affect the elimination function of the liver.
As mentioned previously, earlier attempts to measure hepatic function by determining the serum concentration of exogenous chemical entities such as bromosulfalein or indocyanine green (J. Caesar et al., The Use of Indocyanine Green in the Measurement of Hepatic Blood Flow and as a Test of Hepatic Function, Clin. Sci., 1961, 21, 43-57; A. W. Hemming et al., Indocyanine Green Clearance as a Predictor of Successful Hepatic Resection in Cirrhotic Patients, Am. J. Surg., 1992, 163, 515-518) were non-specific, singular, and required intermittent blood sampling for assessment. Subsequently, non-invasive techniques for assessing hepatic function by continuously monitoring indocyanine green (ICG) clearance from blood have been developed by us and by others and references describing these techniques are incorporated herein by reference (C. M. Leevy et al., Indocyanine Green Clearance as a Test for Hepatic Function: Evaluation by Dichromatic Ear Densitometry, Journal of Medicine, 1993, 24, 10-27; M. Kanda et al., Continuous Monitoring of Cardiogreen Removal by a Diseased Liver Using an Optical Sensor, Proc. SPIE, 1988, 904, 39-46; M. Kanda and S. Niwa, Development of a Noninvasive Monitoring Instrument for Serum Indocyanine Green Dye Concentration", Applied Optics, 1992, 31, 6668-6675; S. Shimizu et al., New Method for Measuring ICG Rmax with a Clearance Meter, World J. Surg., 1995, 19, 113-118; R. B. Dorshow et al., Non-Invasive Fluorescence Detection of Hepatic and Renal Function, Bull. Am. Phys. Soc. 1997, 42, 681).
Serum creatinine measured at frequent intervals by clinical laboratories is currently the most common way of assessing renal function and following the dynamic changes in renal function which occur in critically ill patients (J. B. Henry (Ed). Clinical Diagnosis and Management by Laboratory Methods, 17th Edition, W. B. Saunders, Philadelphia, Pa., 1984); C. E. Speicher, The right test: A physician's guide to laboratory medicine, W. B. Saunders, Philadelphia, Pa., 1989). These values are frequently misleading since the value is affected by age, state of hydration, renal perfusion, muscle mass, dietary intake, and many other anthropometric and clinical variables. Further, a single value returned several hours after sampling is difficult to correlate with other important physiologic events such as blood pressure, cardiac output, state of hydration and other specific clinical events (e.g., hemorrhage, bacteremia, ventilator settings and others). An approximation of glomerular filtration rate can be made via a 24 hour urine collection. This requires 24 hours to collect, several more hours to analyze, a serum sample at some point in the 24 hours, and meticulous bedside collection technique. New or repeat data are equally cumbersome to obtain. At times, changes in serum creatinine must be further clarified by values for urinary electrolytes, osmolality, and derived calculations such as the "renal failure index" or the "fractional excretion of sodium." These require additional samples of serum collected contemporaneously with urine samples and, after a delay, precise calculations. Many times, dosing of medication is adjusted for renal function and thus can be equally as inaccurate, equally delayed, and as difficult to reassess as the values upon which they are based. Lastly, clinical decisions in the critically ill population are often equally as important in their timing as they are in their accuracy.
Thus the availability of a real-time, accurate, repeatable measure of glomerular filtration rate under specific yet changing circumstances represents a substantial improvement over any currently available or widely practiced method. Moreover, since the method depends solely on the renal elimination of the exogenous chemical entity, the measurement is absolute and requires no subjective interpretation based on age, muscle mass, blood pressure, etc. In fact it represents the nature of renal function in this particular patient, under these particular circumstances, at this precise moment in time.
Recently, assessment of renal function by continuously monitoring the blood clearance of exogenous optical, radiometric, or magnetic markers such as fluorescein-inulin and fluorescein-succinylated polylysine conjugates, chromium-51 ethylenediamine tetraacetate complex, and gadolinium diethylenetriamine pentaacetate complex have been developed by us and by others and are incorporated herein as reference (R. B. Dorshow et al., Non-Invasive Fluorescence Detection of Hepatic and Renal Function, Bull. Am. Phys. Soc. 1997, 42, 681); M. F. Tweedle et al., A Noninvasive Method for Monitoring Renal Status at Bedside, Investigative Radiology, 1997, 32, 802-805; M. Sohtell et al., FITC-Inulin as a Kidney Tubule Marker in the Rat, Acta. Physiol. Scand., 1983, 119, 313-316; and M. Rehling et al., Simultaneous Measurement of Renal Clearance of .sup.99m Tc-Labelled Diethylenetriamine-pentaacetic acid, .sup.51 Cr-labelled Ethylenediamine-tetraacetate and Inulin in Man, Clin. Sci., 1984, 66, 613-619).
Thus, there remains a need in the art for methods of measuring physiological function of many organs at once to reduce the risk of fatality due to multiple organ failure.
In addition, the invention may also be used to evaluate hypercholesterolemia. Clearance rate measurements may allow the clinician to determine whether high serum cholesterol resulted from increased rate of LDL production or from decreased rate of LDL clearance, which may impact therapy. The invention may also be used to measure cardiac output. The ability to concurrently measure cardiac function while also measuring hepatic and renal function may allow the clinician to draw preliminary conclusions about whether any observed changes in hepatic and renal functions were due to primary renal or hepatic disease or secondary to heart disease.